Adaptive Nutrition Intervention Stabilizes Serum Phosphorus Levels in Hemodialysis Patients: A Multicenter Decentralized Clinical Trial Using Real-World Data.

OBJECTIVE: This study aims to evaluate the effect of an adaptive nutritional and educational intervention for patients on hemodialysis (HD) in a routine care setting, using real-world data from electronic health records. METHODS: Decentralized clinical trial of seven HD facilities recruited patients who have been on HD for over 3 months (N = 153) for an 8-week adaptive intervention protocol. Patients were divided into four groups: (1) control (2) education intervention (3) meal intervention (4) education and meal interventions. Educational contents were digitally delivered via mobile phones and premade meals tailored on laboratory findings were home-delivered. Changes in serum electrolytes and malnutrition inflammation score (MIS) were analyzed. RESULTS: Meal intervention statistically significantly stabilized serum phosphorus level (ß = -0.81 mg/dL, 95% confidence interval = [-1.40, -0.22]) at week 8, with increased likelihood of being within target serum value range (odds ratio = 1.21, 95% confidence interval = [1.04, 1.40]). Meal group showed better nutritional status (MIS = 3.65) than the education group (MIS = 5.10) at week 8 (adjusted p < .05). No significant changes were observed in serum potassium level, depression, and self-efficacy. CONCLUSION: It was demonstrated that an adaptive meal intervention in a real-world care setting may benefit serum phosphorus control and nutritional status of patients on HD, without negative effect on depression levels or self-efficacy. More work is needed to develop an effective educational intervention.

Digital Health Equity and Tailored Health Care Service for People With Disability: User-Centered Design and Usability Study.

BACKGROUND: As digital health services advance, digital health equity has become a significant concern. However, people with disability and older adults still face health management limitations, particularly in the COVID-19 pandemic. An essential area of investigation is proposing a patient-centered design strategy that uses patient-generated health data (PGHD) to facilitate optimal communication with caregivers and health care service providers. OBJECTIVE: This study aims to conceptualize, develop, and validate a digitally integrated health care service platform for people with disability, caregivers, and health care professionals, using Internet of Things devices and PGHD to contribute to improving digital health equity. METHODS: The methodology consists of 5 stages. First, a collaborative review of the previous app, Daily Healthcare 1.0, was conducted with individuals with disabilities, caregivers, and health care professionals. Secondly, user needs were identified via personas, scenarios, and user interface sketches to shape a user-centered service design. The third stage created an enhanced app that integrated these specifications. In the fourth stage, heuristic evaluations by clinical and app experts paved the way for Daily Healthcare 2.0, now featuring Internet of Things device integration. Conclusively, in the fifth stage, an extensive 2-month usability evaluation was executed with user groups comprising individuals with disabilities using the app and their caregivers. RESULTS: Among the participants, "disability welfare information and related institutional linkage" was the highest priority. Three of the 14 user interface sketches the participants created were related to "providing educational content." The 11 heuristic evaluation experts identified "focusing on a single task" as a crucial issue and advocated redesigning the home menu to simplify it and integrate detailed menus. Subsequently, the app Daily Healthcare 2.0 was developed, incorporating wearable devices for collecting PGHD and connecting individuals with disabilities, caregivers, and health care professionals. After the 2-month usability evaluation with 27 participants, all participants showed an increase in eHealth literacy, particularly those who used the caregiver app. Relatively older users demonstrated improved scores in health IT usability and smartphone self-efficacy. All users' satisfaction and willingness to recommend increased, although their willingness to pay decreased. CONCLUSIONS: In this study, we underscore the significance of incorporating the distinct needs of individuals with disabilities, caregivers, and health care professionals from the design phase of a digital health care service, highlighting its potential to advance digital health equity. Our findings also elucidate the potential benefits of fostering partnerships between health consumers and providers, thereby attenuating the vulnerability of marginalized groups, even amid crises such as the COVID-19 pandemic. Emphasizing this imperative, we advocate for sustained endeavors to bolster the digital literacy of individuals with disabilities and champion collaborative cocreation, aiming to uphold the collective ethos of health and digital health equity.

Statement on chronotherapy for the treatment of hypertension: consensus document from the Korean society of hypertension.

Nocturnal blood pressure (BP) has been shown to have a significant predictive value for cardiovascular disease. In some cases, it has a superior predictive value for future cardiovascular outcomes than daytime BP. As efficacy of BP medications wanes during nighttime and early morning, control of nocturnal hypertension and morning hypertension can be difficult. As such, chronotherapy, the dosing of BP medication in the evening, has been an ongoing topic of interest in the field of hypertension. Some studies have shown that chronotherapy is effective in reducing nocturnal BP, improving non dipping and rising patterns to dipping patterns, and improving cardiovascular prognosis. However, criticism and concerns have been raised regarding the design of these studies, such as the Hygia study, and the implausible clinical benefits in cardiovascular outcomes considering the degree of BP lowering from bedtime dosing. Studies have shown that there is no consistent evidence to suggest that routine administration of antihypertensive medications at bedtime can improve nocturnal BP and early morning BP control. However, in some cases of uncontrolled nocturnal hypertension and morning hypertension, such as in those with diabetes mellitus, chronic kidney disease, and obstructive sleep apnea, bedtime dosing has shown efficacy in reducing evening and early morning BP. The recently published the Treatment in Morning versus Evening (TIME) study failed to demonstrate benefit of bedtime dosing in reducing cardiovascular outcomes in patients with hypertension. With issues of the Hygia study and negative results from the TIME study, it is unclear at this time whether routine bedtime dosing is beneficial for reducing cardiovascular outcomes.

Efficacy and Safety of SID142 in Patients With Peripheral Arterial Disease: A Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group, Phase III Clinical Trial.

PURPOSE: Renexin® is a combination pill of cilostazol and Ginkgo biloba leaf extract that is used for the improvement of ischemic symptoms associated with peripheral arterial disease (PAD). SID142 is a controlled-release tablet of cilostazol (200 mg) and G biloba leaf extract (160 mg) that was developed to address the limitation of BID administration with Renexin. This study aimed to verify that SID142 was not inferior to Renexin in the treatment of patients with PAD. METHODS: This was a multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III clinical trial. Study subjects were randomized to receive SID142 once daily or Renexin twice a day for 12 weeks. The primary end point was a change in the patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. If the lower limit of the two-sided 95% CI was greater than -10, the study drug was declared noninferior to the reference drug. Secondary efficacy end points included cold sensation, ankle-brachial index, ankle systolic pressure, maximum walking distance, pain-free walking distance, and investigator's global assessment. Study group results were compared 4, 8, and 12 weeks after treatment. Adverse events were assessed as a safety end point. FINDINGS: In total, 344 subjects from 19 medical centers were screened, and a total of 170 subjects were randomly assigned to either the SID142 (n = 86) or the Renexin (n = 84) group. Analysis of the change in lower extremity pain at 12 weeks compared with baseline revealed that SID142 was not inferior to Renexin (21.44 [19.23] vs 22.30 [17.75]; 95% CI, -7.70 to 5.97; P = 0.5942). No significant differences were found between groups in any secondary efficacy end point. However, the incidence of adverse reactions was significantly lower in the SID142 group (22.35% vs 39.29%; P = 0.0171). IMPLICATIONS: SID142 once daily was not inferior to Renexin twice a day for efficacy in patients with PAD. SID142 had a favorable safety profile. CLINICALTRIALS: gov identifier: NCT03318276.

Preclinical Evaluation of a Novel Polymer-free Everolimus-eluting Stent in a Mid-term Porcine Coronary Restenosis Model.

BACKGROUND: Titanium dioxide films exhibit good biocompatibility and may be effective as drug-binding matrices for drug-eluting stents. We conducted a mid-term evaluation of a novel polymer-free everolimus-eluting stent using nitrogen-doped titanium dioxide film deposition (TIGEREVOLUTION®) in comparison with a commercial durable polymer everolimus-eluting stent (XIENCE Alpine®) in a porcine coronary restenosis model. METHODS: Twenty-eight coronary arteries from 14 mini-pigs were randomly allocated to TIGEREVOLUTION® stent and XIENCE Alpine® stent groups. The stents were implanted in the coronary artery at a 1.1-1.2:1 stent-to-artery ratio. Eleven stented coronary arteries in each group were finally analyzed using coronary angiography, optical coherence tomography, and histopathologic evaluation 6 months after stenting. RESULTS: Quantitative coronary analysis showed no significant differences in the pre-procedural, post-procedural, and 6-month lumen diameters between the groups. In the volumetric analysis of optical coherence tomography at 6 months, no significant differences were observed in stent volume, lumen volume, and percent area stenosis between the groups. There were no significant differences in injury score, inflammation score, or fibrin score between the groups, although the fibrin score was zero in the TIGEREVOLUTION® stent group (0 vs. 0.07 ± 0.11, P = 0.180). CONCLUSION: Preclinical evaluation, including optical coherence tomographic findings 6 months after stenting, demonstrated that the TIGEREVOLUTION® stent exhibited efficacy and safety comparable with the XIENCE Alpine® stent, supporting the need for further clinical studies on the TIGEREVOLUTION® stent.

Predicting treatable traits for long-acting bronchodilators in patients with stable COPD.

PURPOSE: There is currently no measure to predict a treatability of long-acting ß-2 agonist (LABA) or long-acting muscarinic antagonist (LAMA) in patients with chronic obstructive pulmonary disease (COPD). We aimed to build prediction models for the treatment response to these bronchodilators, in order to determine the most responsive medication for patients with COPD. METHODS: We performed a prospective open-label crossover study, in which each long-acting bronchodilator was given in a random order to 65 patients with stable COPD for 4 weeks, with a 4-week washout period in between. We analyzed 14 baseline clinical traits, expression profiles of 31,426 gene transcripts, and damaged-gene scores of 6,464 genes acquired from leukocytes. The gene expression profiles were measured by RNA microarray and the damaged-gene scores were obtained after DNA exome sequencing. Linear regression analyses were performed to build prediction models after using factor and correlation analyses. RESULTS: Using a prediction model for a LABA, traits found associated with the treatment response were post-bronchodilator forced expiratory volume in 1 second, bronchodilator reversibility (BDR) to salbutamol, expression of three genes (CLN8, PCSK5, and SKP2), and damage scores of four genes (EPG5, FNBP4, SCN10A, and SPTBN5) (R2=0.512, p<0.001). Traits associated with the treatment response to a LAMA were COPD assessment test score, BDR, expression of four genes (C1orf115, KIAA1618, PRKX, and RHOQ) and damage scores of three genes (FBN3, FDFT1, and ZBED6) (R2=0.575, p<0.001). The prediction models consisting only of clinical traits appeared too weak to predict the treatment response, with R2=0.231 for the LABA model and R2=0.121 for the LAMA model. CONCLUSION: Adding the expressions of genes and damaged-gene scores to the clinical traits may improve the predictability of treatment response to long-acting bronchodilators.

Tpeak-Tend interval during therapeutic hypothermia can predict upcoming ventricular fibrillation in subjects with aborted arrhythmic sudden cardiac death: 3-years follow-up results.

AIMS: Prolonged Tpeak-Tend interval has been shown to be markers of arrhythmogenesis in various cardiac disorders. However, its dynamicity is one of the obstacles to predict fatal ventricular arrhythmia. This study investigated whether Tpeak-Tend interval during therapeutic hypothermia (TH) is associated with ventricular fibrillation (VF) inducibility and clinical arrhythmia in subjects with aborted arrhythmic sudden cardiac death (SCD). METHODS AND RESULTS: The study group included 31 patients (24 males, age 39.1 ± 17.6 years) presenting with arrhythmic SCD in whom Tpeak-Tend interval and J-wave amplitude were measured in electrocardiogram (ECG) of the earliest medical contact and during TH; these patients underwent programmed ventricular stimulation. The summation of J-wave amplitude and QTc interval increased during TH. However, it was not associated with VF inducibility. Patients with inducible VF showed a small Tpeak-Tend interval dispersion in the baseline 12-lead ECG (68.8 ± 24.7 vs. 94.0 ± 55.6 ms, P = 0.044) and a marked increase of the dispersion during the TH (36.2 ± 51.2 vs. -6.1 ± 45.5 ms, P = 0.039). Twenty-four patients underwent implantable cardioverter defibrillator (ICD) implantation. Among them, the patients with long QTc, Tpeak-Tend, and precordial Tpeak-Tend during the TH developed VF more frequently (QTc, 511.9 ± 53.71 ms vs. 566.5 ± 56.08 ms, P = 0.038; Tpeak-Tend interval, 145.6 ± 38.4 ms vs. 185.7 ± 49.95 ms, P = 0.048; precordial Tpeak-Tend interval, 139.3 ± 35.11 ms vs. 185.7 ± 49.95 ms, P = 0.018). The initial VF inducibility was not related with the VF development in follow-up. CONCLUSION: In patients with aborted arrhythmic SCD, long Tpeak-Tend interval and QTc interval during TH could predict VF development in their follow-up.

Effects of combination therapy of statin and N-acetylcysteine for the prevention of contrast-induced nephropathy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: Acute myocardial infarction (AMI) is a risk factor for contrast-induced nephropathy (CIN). We investigated whether pretreatment with statin, N-acetylcysteine (NAC) and sodium bicarbonate (NaHCO3) reduces the risk of CIN. METHODS: We conducted a prospective trial and enrolled a total of 334 ST-segment elevation myocardial infarction (STEMI) patients. Patients were divided into four groups: Group I (statin 40mg), Group II (statin 80mg), Group III (statin 80mg plus NAC 1200mg) and Group IV (regimen of group III plus NaHCO3 154mEq/L). CIN was defined as ≥25% or ≥0.5mg/dL increase in serum creatinine from the baseline within the 72h after PCI. RESULTS: CIN occurred in 72 (21.6%) patients. The incidence of CIN was the lowest in the group III (14.3%), and multivariate analysis showed the lower incidence of CIN in group III compared to Group I [odds ratio (OR) 0.29, 95% confidence interval (CI) 0.13-0.64, p=0.002]. Admission hyperglycemia [(AHG)>198mg/dL] (OR 2.20, 95% Cl 1.20-3.68, p=0.011) and the use of intra-aortic balloon pump (IABP) (OR 4.20, 95% CI 1.38-12.78, p=0.016) were independent predictors for CIN. The CIN (OR 9.00, 95% CI 1.30-62.06, p=0.026) was an independent predictor for in-hospital mortality. CONCLUSIONS: Combination of high-dose statin plus NAC was associated with lower incidence of CIN in patients with STEMI who underwent primary PCI compared to statin only.

Safety of the Up-titration of Nifedipine GITS and Valsartan or Low-dose Combination in Uncontrolled Hypertension: the FOCUS Study.

PURPOSE: Doubling the dose of antihypertensive drugs is necessary to manage hypertension in patients whose disease is uncontrolled. However, this strategy can result in safety issues. This study compared the safety and efficacy of up-titration of the nifedipine gastrointestinal therapeutic system (GITS) with up-titration of valsartan monotherapy; these were also compared with low-dose combinations of the two therapies. METHODS: This prospective, open-label, randomized, active-controlled, multicenter study lasted 8 weeks. If patients did not meet the target blood pressure (BP) after 4 weeks of treatment with low-dose monotherapy, they were randomized to up-titration of the nifedipine GITS dose from 30 mg (N30) to 60 mg or valsartan from 80 mg to 160 mg or they were randomized to receive a low-dose combination of N30 and valsartan 80 mg for another 4 weeks. BP variability was assessed by using the SD or the %CV of the short-term BP measured at clinic. FINDINGS: Of the 391 patients (20~70 years with stage II or higher hypertension) screened for study inclusion, 362 patients who had 3 BP measurements were enrolled. The reduction in the mean systolic/diastolic BP from baseline to week 4 was similar in both low-dose monotherapy groups with either N30 or valsartan 80 mg. BP variability (SD) was unchanged with either therapy, but the %CV was slightly increased in the N30 group. There was no significant difference in BP variability either in SD or %CV between responders and nonresponders to each monotherapy despite the significant difference in the mean BP changes. The up-titration effect of nifedipine GTS from 30 to 60 mg exhibited an additional BP reduction, but this effect was not shown in the up-titration of valsartan from 80 to 160 mg. Although the difference in BP was obvious between high-dose nifedipine GTS and valsartan, the BP variability was unchanged between the 2 drugs and was similar to the low-dose combinations. There was a low rate of adverse events in all treatment groups. In addition, escalating the dose of either nifedipine GITS or valsartan revealed a similar occurrence of adverse effects with low-dose monotherapy or the low-dose combination. IMPLICATIONS: Compared with up-titration of the angiotensin receptor blocker valsartan, up-titration of the calcium channel blocker nifedipine GITS provided no additional increased safety concerns and revealed better mean reductions in BP without affecting short-term BP variability. ClinicalTrials.gov identifier: NCT01071122.

Sphingomonas kyeonggiense sp. nov., isolated from soil of a ginseng field.

A Gram-staining negative bacterium, THG-DT81(T), which was isolated from soil of a ginseng field, was investigated using a polyphasic taxonomic approach. Cells were oxidase- and catalase-positive, aerobic, rod-shaped and motile with one polar flagellum. Strain THG-DT81(T) grew optimally at pH 7.0 and in the absence of NaCl on trypticase soy agar. Its optimum growth temperature was 25-28 °C. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain THG-DT81(T) belongs to the family Sphingomonadaceae and was related to Sphingomonas pituitosa EDIV(T) (98.0 % similarity), S. leidyi ATCC 15260(T) (97.8 %), S. trueperi LMG 2142(T) (97.1 %), S. azotifigens NBRC 15497(T) (97.1 %), S. koreensis JSS26 (T) (97.1 %) and S. dokdonensis DS-4(T) (97.0 %). Strain THG-DT81(T) contained Q-10 as the predominant ubiquinone and C18:1 ω7c and C16:0 as the major fatty acids. The G+C content of the genomic DNA was determined to be 66.8 mol %. The major component in the polyamine pattern was identified as sym-homospermidine. The major polar lipids detected in strain THG-DT81(T) were sphingoglycolipid, phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylcholine. The DNA-DNA relatedness values of the strain THG-DT81(T) and its closest phylogenetically neighbors were below 21 %. The phenotypic characteristics and genotypic data demonstrated the affiliation of strain THG-DT81(T) to the genus Sphingomonas. On the basis of the polyphasic taxonomic data presented, strain THG-DT81(T) is described as a novel species of genus Sphingomonas, for which the name Sphingomonas kyeonggiense sp. nov. is proposed. The type strain is THG-DT81(T) (= KACC 17173(T) = JCM 18825(T)).

Incorporating inter-relationships between different levels of genomic data into cancer clinical outcome prediction.

In order to improve our understanding of cancer and develop multi-layered theoretical models for the underlying mechanism, it is essential to have enhanced understanding of the interactions between multiple levels of genomic data that contribute to tumor formation and progression. Although there exist recent approaches such as a graph-based framework that integrates multi-omics data including copy number alteration, methylation, gene expression, and miRNA data for cancer clinical outcome prediction, most of previous methods treat each genomic data as independent and the possible interplay between them is not explicitly incorporated to the model. However, cancer is dysregulated by multiple levels in the biological system through genomic, epigenomic, transcriptomic, and proteomic level. Thus, genomic features are likely to interact with other genomic features in the different genomic levels. In order to deepen our knowledge, it would be desirable to incorporate such inter-relationship information when integrating multi-omics data for cancer clinical outcome prediction. In this study, we propose a new graph-based framework that integrates not only multi-omics data but inter-relationship between them for better elucidating cancer clinical outcomes. In order to highlight the validity of the proposed framework, serous cystadenocarcinoma data from TCGA was adopted as a pilot task. The proposed model incorporating inter-relationship between different genomic features showed significantly improved performance compared to the model that does not consider inter-relationship when integrating multi-omics data. For the pair between miRNA and gene expression data, the model integrating miRNA, for example, gene expression, and inter-relationship between them with an AUC of 0.8476 (REI) outperformed the model combining miRNA and gene expression data with an AUC of 0.8404. Similar results were also obtained for other pairs between different levels of genomic data. Integration of different levels of data and inter-relationship between them can aid in extracting new biological knowledge by drawing an integrative conclusion from many pieces of information collected from diverse types of genomic data, eventually leading to more effective screening strategies and alternative therapies that may improve outcomes.

Taibaiella koreensis sp. nov., isolated from soil of a ginseng field.

A Gram-staining-negative, strictly aerobic, motile (by gliding), non-spore-forming and rod-shaped bacterial strain, designated THG-DT86(T), was isolated from soil of a ginseng field of Pocheon province in the Republic of Korea and its taxonomic position was investigated by a polyphasic approach. Growth occurred at 10-35 °C, at pH 6.5-8.5 and with 0-1.5 % (w/v) NaCl on trypticase soy agar. Flexirubin-type pigments were found to be present. On the basis of 16S rRNA gene sequence similarity, strain THG-DT86(T) was shown to belong to the genus Taibaiella and was related to Taibaiella smilacinae PTJT-5(T) (95.3 %). The G+C content of the genomic DNA was 50.1 mol%. The only isoprenoid quinone detected in strain THG-DT86(T) was menaquinone-7 (MK-7) and the only polyamine was homospermidine. The predominant fatty acids were iso-C15 : 0, iso-C17 : 0 3-OH, C16 : 0, iso-C15 : 1 G and iso-C17 : 0, and the major polar lipids were phosphatidylethanolamine, an unidentified aminophosphoglycolipid and an unidentified aminophospholipid. Phenotypic data and phylogenetic inference supported the affiliation of strain THG-DT86(T) to the genus Taibaiella, and a number of biochemical tests differentiated strain THG-DT86(T) from the recognized species of the genus Taibaiella. Therefore, the novel isolate represents a novel species, for which the name Taibaiella koreensis sp. nov. is proposed, with THG-DT86(T) as the type strain ( = KACC 17171(T) = JCM 18823(T)).

Yin and Yang of disease genes and death genes between reciprocally scale-free biological networks.

Biological networks often show a scale-free topology with node degree following a power-law distribution. Lethal genes tend to form functional hubs, whereas non-lethal disease genes are located at the periphery. Uni-dimensional analyses, however, are flawed. We created and investigated two distinct scale-free networks; a protein-protein interaction (PPI) and a perturbation sensitivity network (PSN). The hubs of both networks exhibit a low molecular evolutionary rate (P < 8 × 10(-12), P < 2 × 10(-4)) and a high codon adaptation index (P < 2 × 10(-16), P < 2 × 10(-8)), indicating that both hubs have been shaped under high evolutionary selective pressure. Moreover, the topologies of PPI and PSN are inversely proportional: hubs of PPI tend to be located at the periphery of PSN and vice versa. PPI hubs are highly enriched with lethal genes but not with disease genes, whereas PSN hubs are highly enriched with disease genes and drug targets but not with lethal genes. PPI hub genes are enriched with essential cellular processes, but PSN hub genes are enriched with environmental interaction processes, having more TATA boxes and transcription factor binding sites. It is concluded that biological systems may balance internal growth signaling and external stress signaling by unifying the two opposite scale-free networks that are seemingly opposite to each other but work in concert between death and disease.

Hair growth activity of Crataegus pinnatifida on C57BL/6 mouse model.

Crataegus pinnatifida has a long history of use in traditional oriental herbal medicine to stimulating digestion and improving blood circulation. Based on nutrition of hair, the present study was conducted to assess the effect of C. pinnatifida extract on hair growth using mouse model and its mechanisms of action. The C. pinnatifida extract containing the contents of total polyphenol of 5.88□0.82 g gallic acid/100 g extract and proanthocyanidin of 9.15□1.58 mg cyaniding chloride/100 g extract was orally administered daily at a dosage of 50 mg/kg weight to the 7-week-old C57BL/6 mice in telogen. The C. pinnatifida extract promoted hair growth by inducing anagen phase in mice in telogen, reflected by color of skin, thickness of hair shaft, and density of hair. The ratio of anagento telogen was determined by shape of hair follicles in vertically sectioned slide and increased by oral administration of C. pinnatifida extract. The number and the size of hair follicles were also enlarged, indicating anagen phase induction. The proliferation of human dermal papilla cells (hDPC) was accelerated by addition of C. pinnatifida extract, which activated the signaling of mitogen-activated protein kinases (Erk, p-38, and JNK) and Akt. Moreover, the ratio of Bcl-2/Bax as the determinant of cell fate was also raised in skin. These results suggest that the C. pinnatifida extract promotes hair growth by inducing anagen phase, which might be mediated by the activation of cellular signalings that enhance the survival of cultured hDPC and the increase of the ratio of Bcl-2 to Bax that protects cells against cell death.

Gene expression profiling of murine hepatic steatosis induced by tamoxifen.

Tamoxifen is an antiestrogenic agent used widely in the treatment of estrogen receptor-positive breast cancer. However, hepatic steatosis has been reported during clinical trials of tamoxifen. To explore the mechanism responsible for this tamoxifen-induced hepatic steatosis, we used microarray analysis to profile the gene expression pattern of mouse liver after tamoxifen treatment. Tamoxifen was administered orally as a single dose of 10mg/kg (low dose), 50mg/kg (medium dose), or 100mg/kg (high dose) to C57BL/6 mice, and the livers were removed 2h, 4h, 8h, and 24h later. From microarray data obtained from the liver samples, 414 genes were selected as tamoxifen-responsive genes (P<0.05, two-way ANOVA; cutoff ≥ 1.5-fold response). These genes were classified into three groups: 308 of the 414 genes showed a time-dependent response, nine genes showed a dose-dependent response, and 97 genes showed a time- and dose-dependent response. Most of the 308 time-dependent-responsive genes were associated predominantly with the biological processes involved in lipid metabolism. Overrepresented transcription factor binding site analysis showed that the following nuclear receptors that are important in lipid and carbohydrate metabolism were overrepresented: the androgen receptor (AR), nuclear receptor subfamily 2 group F member 1 (NR2F1), hepatocyte nuclear factor 4α (HNF4α), and retinoic acid receptor-related orphan receptor alpha 1 (RORα1). Reporter gene analysis further revealed that tamoxifen repressed the 5α-dihydrotestosterone-induced activation of the AR and the intrinsic transactivation function of RORα1, HNF4α, and NR2F1. Taken together, these data provide a better understanding of the molecular mechanism underlying tamoxifen-induced steatogenic hepatotoxicity and useful information for predicting steatogenic hepatotoxicity.

Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice.

Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p<0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed >or=2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.

Gene expression profiles of murine fatty liver induced by the administration of valproic acid.

Valproic acid (VPA) has been used as anticonvulsants, however, it induces hepatotoxicity such as microvesicular steatosis and necrosis in the liver. To explore the mechanisms of VPA-induced steatosis, we profiled the gene expression patterns of the mouse liver that were altered by treatment with VPA using microarray analysis. VPA was orally administered as a single dose of 100 mg/kg (low-dose) or 1000 mg/kg (high-dose) to ICR mice and the animals were killed at 6, 24, or 72 h after treatment. Serum alanine aminotransferase and aspartate aminotransferase levels were not significantly altered in the experimental animals. However, symptoms of steatosis were observed at 72 h with low-dose and at 24 h and 72 h with high-dose. After microarray data analysis, 1910 genes were selected by two-way ANOVA (P<0.05) as VPA-responsive genes. Hierarchical clustering revealed that gene expression changes depended on the time rather than the dose of VPA treatment. Gene profiling data showed striking changes in the expression of genes associated with lipid, fatty acid, and steroid metabolism, oncogenesis, signal transduction, and development. Functional categorization of 1156 characteristically up- and down-regulated genes (cutoff >1.5-fold) revealed that 60 genes were involved in lipid metabolism that was interconnected with biological pathways for biosynthesis of triglyceride and cholesterol, catabolism of fatty acid, and lipid transport. This gene expression profile may be associated with the known steatogenic hepatotoxicity of VPA and it may provide useful information for prediction of hepatotoxicity of unknown chemicals or new drug candidates through pattern recognition.

The effects of QRS duration and pacing sites on the acute hemodynamic changes during right ventricular pacing.

BACKGROUND: Has been reported that patients exhibiting prolonged paced QRS duration tend to have more serious heart disease, and the paced QRS duration can be an effective indicator of impaired left ventricular function. However, the acute and chronic hemodynamic effects of paced QRS duration and pacing sites during right ventricular (RV) pacing remain unknown. METHODS: A total of 14 patients who underwent electrophysiologic study for paroxysmal supraventricular tachycardia were examined. RV pacing was performed at 10 different sites with cycle lengths of 600 ms and 500 ms utilizing a 6-7F deflectable quadripolar electrode catheter. Systolic, diastolic, and mean blood pressures during pacing were measured once the blood pressure was stabilized. RESULTS: During RV pacing, blood pressures (systolic/diastolic/mean) decreased. The change of post-pacing QRS duration and pre-pacing the systolic blood pressure (SBP) were greater in the group with paced QRS duration. The differences overall were greater than 140 ms. The SBP decrease during pacing was larger in the group exhibiting paced QRS duration of greater than 140 ms. The SBP decrease during pacing showed relation to QRS duration during pacing (r = 0.500, p = 0.001), the change of QRS duration post-pacing (r = 0.426, p = 0.001), and SBP during sinus rhythm (r = 0.342, p = 0.001) on linear correlation analysis. The pacing site, on the other hand, did not affect acute hemodynamic changes during pacing. CONCLUSION: Ventricular pacing of less than 40 ms at the area of paced QRS duration is recommended.